L-biopterin is known in the art as a raw material for the preparation of sapropterin hydrochloride (hydrochloride salt of L-tetrahydrobiopterin). Sapropterin hydrochloride is a drug used for the treatment of atypical hyperphenylalaninemia. Although sapropterin hydrochloride is typically prepared by reducing L-biopterin, there is a growing need for the development of an improved method for the preparing of this starting material, namely L-biopterin, in a manner suited to its large scale production.
Heretofore, it is known to prepare L-biopterin using 1′,1′-diethylsulfonyl-L-rhamnose (REM oxide) as its starting material and going through a phenylhydrazone compound as its intermediate product. (See nonpatent literature 1.)
Methods known in the prior art for synthesizing this phenylhydrazone compound as an synthetic intermediate of L-biopterin include obtaining the phenylhydrazone compound from L-rhamnose as a starting material via L-rhamnose diethyl mercaptal (REM) and then 5-deoxy-L-arabinose (5-DA) as intermediate products (See patent literature 1 and nonpatent literature 2.), obtaining the phenylhydrazone compound from L-arabinose through 5-DA (See patent literature 2.), obtaining the phenylhydrazone compound from tartaric acid (See nonpatent literatures 3 and 4.), and obtaining the phenylhydrazone compound from R-ribose (See patent literature 3.).
However, the prior art method of preparing the phenylhydrazone compound ribose from tartaric acid or R-ribose is not adequate for industrial scale production in that such a method involves a longer process and a lower yield and that a low-temperature step or silica gel refining step is involved in the process. Meanwhile, the above-described other method preparing the phenylhydrazone compound from L-rhamnose directly or from L-rhamnose through 5-DA requires such processes that are disadvantageous from a viewpoint of industrial scale production, including water concentrating and resin refining by desalination for 5-DA isolation, and reaction solution concentrating using RO (reverse osmosis) or like equipment.
The resultant phenylhydrazone compound is reacted with an acetylating agent in pyridine to obtain a triacetylated compound, which is then condensed and cyclized with 6-hydroxy-2,4,5-triaminopyrimidine (TAU) in the coexistence of sodium acetate to obtain a biopterin derivative. After oxidized with iodine or other oxidizing agent, the biopterin derivative is subjected to deacetylation (hydrolysis) to produce L-biopterin.
However, the acetylation process used in the prior art described above requires a use of an excessive quantity of pyridine with an enormous increase in quantity of the reaction solution used in the subsequent processes, resulting in decreased productivity. Also, the above-described cyclization provided substantially as a continuation of its preceding process inevitably involves a use of an enormous quantity of the reaction solution, while decreasing its reaction solvent causes a remarkable reduction in yield due to solubility of the TAU. Further, the prior art method just described is not adequate for a large scale industrial production of L-biopterin, because iodine used as an oxidizing agent in its oxidation process is not only costly, but also has sublimatability and toxicity possibly giving rise to problems in respect of working health and wastewater treatment.    [Patent literature 1] Japanese published unexamined patent application JP A S59-186986    [Patent literature 2] European published unexamined patent application EP 0165595    [Patent literature 3] European published unexamined patent application EP 0385338    [Nonpatent literature 1] Helv. Chim. Acta 68(6) 1639-43 (1985)    [Nonpatent literature 2] J. Org. Chem. 1996, 61,.8698-8700    [Nonpatent literature 3] J. Org. Chem. 1997, 62, 4007-4014